Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8(+) T cells

Matas-Rico, E.; Frijlink, E.; Avila, I.V.; Menegakis, A.; Zon, M. van; Morris, A.J.; ... ; Moolenaar, W.H. (2021)

Article / Letter to editor

Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8(+) T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves G alpha(12/13)-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8(+) T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8(+) T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.

• All authors: Matas-Rico, E.; Frijlink, E.; Avila, I.V.; Menegakis, A.; Zon, M. van; Morris, A.J.; Koster, J.; Salgado-Polo, F.; Kivit, S. de; Lanc, T.; Mazzocca, A.; Johnson, Z.; Haanen, J.; Schumacher, T.N.; Perrakis, A.; Verbrugge, I.; Berg, J.H. van den; Borst, J.; Moolenaar, W.H.
• Date: 2021-11-16
• Journal: Cell Reports
• Volume: 37
• Issue: 7
• DOI: doi:10.1016/j.celrep.2021.110013
• Link: http://www.cell.com/article/S2211124721014959/pdf